Obesity associated Type 2 diabetes (T2D) is a major global cause of morbidity and mortality, and yet current therapies are inadequate. The onset of T2D is often preceded by a condition known as insulin resistance in which tissues become increasingly insensitive to the natural hormone, necessitating the need for more insulin secretion by the pancreas. If this compensatory increase does not occur, blood glucose concentrations rise and T2D occurs. Multiple factors contribute to insulin resistance, but inflammation of visceral adipose tissue (VAT) resulting in chronic release of pro-inflammatory cytokines is known to be a major factor. We recently showed that the adaptive immune system plays a fundamental role in regulating this process. Oligoclonal IFN- producing (Th1) CD4+ T cells in VAT overcome the anti-inflammatory effects of Th2 and Treg cells, and activate M1 macrophages. B-2 cells contribute to the development of insulin resistance by overcoming the anti-inflammatory effects of B-1 cells through their activation of VAT Th1 cells and secretion of pathogenic IgG autoantibodies. Studies of obese non-diabetic humans have revealed that the proportion of Th1 T cells in VAT is highly correlated with body mass index and that insulin resistance is linked to a specific autoantibody signature. These findings strongly support our central hypothesis that the development of insulin resistance in obesity has a significant autoimmune component involving cooperative effects of both B cells and T cells. In this project, we propose to more clearly define the mechanisms contributing to adaptive immune regulation of insulin resistance. We will pursue this objective through the following specific aims: 1) Identiy the mechanisms by which B-1 and B-2 cell subsets exert their opposing effects on insulin resistance in DIO mice. 2) Identify immunologic targets that worsen or protect against obesity related insulin resistance in DIO mice. 3) Assess the clinical significance of the autoantibody signature associated with insulin resistance in obese human subjects. The results of these experiments promise to yield new diagnostic and therapeutic modalities to manage this important disease. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is an extremely common yet poorly understood disease that occurs more frequently in obese persons. We have discovered that fatty tissues in obese people are invaded by white blood cells, called T cells and B cells, that help cause diabetes. In this project we will analyze how this occurs, with the goal of developing new means to predict who will develop diabetes and novel ways to prevent and treat it.